title: NLRP3 controls Trypanosoma cruzi infection through a caspase-1-dependent IL-1R-independent NO production.
abstract: Trypanosoma cruzi (T. cruzi) is an intracellular protozoan parasite and the etiological agent of Chagas disease, a chronic infectious illness that affects millions of people worldwide. Although the role of TLR and Nod1 in the control of T. cruzi infection is well-established, the involvement of inflammasomes remains to be elucidated. Herein, we demonstrate for the first time that T. cruzi infection induces IL-1β production in an NLRP3- and caspase-1-dependent manner. Cathepsin B appears to be required for NLRP3 activation in response to infection with T. cruzi, as pharmacological inhibition of cathepsin B abrogates IL-1β secretion. NLRP3(-/-) and caspase1(-/-) mice exhibited high numbers of T. cruzi parasites, with a magnitude of peak parasitemia comparable to MyD88(-/-) and iNOS(-/-) mice (which are susceptible models for T. cruzi infection), indicating the involvement of NLRP3 inflammasome in the control of the acute phase of T. cruzi infection. Although the inflammatory cytokines IL-6 and IFN-γ were found in spleen cells from NLRP3(-/-) and caspase1(-/-) mice infected with T. cruzi, these mice exhibited severe defects in nitric oxide (NO) production and an impairment in macrophage-mediated parasite killing. Interestingly, neutralization of IL-1β and IL-18, and IL-1R genetic deficiency demonstrate that these cytokines have a minor effect on NO secretion and the capacity of macrophages to control T. cruzi infection. In contrast, inhibition of caspase-1 with z-YVAD-fmk abrogated NO production by WT and MyD88(-/-) macrophages and rendered them as susceptible to T. cruzi infection as NLRP3(-/-) and caspase-1(-/-) macrophages. Taken together, our results demonstrate a role for the NLRP3 inflammasome in the control of T. cruzi infection and identify NLRP3-mediated, caspase-1-dependent and IL-1R-independent NO production as a novel effector mechanism for these innate receptors.
authors.affiliation: Centro de Terapia Celular e Molecular (CTC-Mol), Universidade Federal de São Paulo, Vl Clementino, São Paulo, Brazil.
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Gonçalves
authors.forename: Kely C
authors.initials: KC
authors.lastname: Matteucci
authors.forename: Carina L
authors.initials: CL
authors.lastname: Buzzo
authors.forename: Bruna H
authors.initials: BH
authors.lastname: Miollo
authors.forename: Danny
authors.initials: D
authors.lastname: Ferrante
authors.forename: Ana C
authors.initials: AC
authors.lastname: Torrecilhas
authors.forename: Mauricio M
authors.initials: MM
authors.lastname: Rodrigues
authors.forename: Jose M
authors.initials: JM
authors.lastname: Alvarez
authors.forename: Karina R
authors.initials: KR
authors.lastname: Bortoluci
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism*; D014355:Chagas Disease / Q000276:immunology* / Q000469:parasitology; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D053583:Interleukin-1beta / Q000096:biosynthesis*; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009569:Nitric Oxide / Q000378:metabolism*; D014349:Trypanosoma cruzi / Q000276:immunology*
chemical_list: D002352:Carrier Proteins; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D009569:Nitric Oxide; D020170:Caspase 1